TYPE OF INVESTIGATION

QUESTION

(P) In infants 35-42 weeks gestational age, who are at risk for hypoglycemia, (I) does 0.5mL/kg oral 40% dextrose gel and encouraging feeding (C) compared to administration of placebo gel and encouraging feeding (O) lead to decreased treatment failure, as defined by glucose concentration <2.6mmol/L (46mg/dL)?

METHODS

Design: Randomized, double-blind, placebo-controlled clinical trial

Allocation: Concealed by using computer-generated blocked randomization with variable block sizes, allocation ratio of 1:1. Randomization was stratified by maternal diabetes (yes/no) and birth weight (small, appropriate or large for gestational age). Twins were assigned independently.

Blinding: Identical dextrose and placebo gel packs were prepared by an independent hospital pharmacist. Clinicians, families and investigators were blinded to group assignment.

Follow-up period: In this study, infants were followed through to two weeks to determine rates of formula and breast feeding.

Setting: Single tertiary referral center in New Zealand

Patients: Infants 35-42 weeks gestation age, less than 48-hours old who were identified to have risk factors for hypoglycemia including being an infant of a diabetic mother (IDM including gestational, Type 1 or 2 diabetes), preterm (35 or 36 weeks), small (birth weight <10%ile or <2500g), large (birth weight >90%ile or >4500g) or other reasons including poor feeding. If an infant was previously treated for neonatal hypoglycemia, had congenital malformations, a terminal disorder, or a skin condition preventing the use of continuous glucose monitoring they were excluded.

Intervention: Hypoglycemic infants were randomized to either the treatment group (0.5mL/kg oral 40% dextrose) or control group (placebo gel) with a blood or interstitial glucose concentration of <2.6mmol/L. Blood glucose concentration was re-measured 30 minutes after treatment. For infants who were persistently hypoglycemic or had recurrent hypoglycemia, additional doses of gel were administered up to a maximum of six doses within 48 hours.

Secondary outcomes: Pre-specified secondary outcomes included admission to the neonatal intensive care unit (NICU), frequency of breastfeeding, total volume and frequency of expressed breastmilk and formula, intravenous dextrose and dextrose gel use within the first 48-hours of life, formula and breast milk feeding rates at 2 weeks of age, incidence of rebound and recurrent hypoglycemia, time taken to achieve interstitial glucose concentrations of 2.6mmol/L after treatment and total duration of interstitial glucose concentrations <2.6mmol/L up to 48-hours after birth.

Analysis and Sample Size: The study was deigned as a one-tailed study (alpha-level 0.05) with 80% power with goal sample size of 230 infants to detect a decrease in the treatment failure rate from an estimated 35% in the placebo group to 20% in the treatment group. Standard two-sided analysis was preformed with t-tests for normally distributed continuous variables and Wilcoxon two-sample test for other variables. The primary outcome was adjusted for maternal diabetes and birth weight (reasons why the infant was at risk for neonatal hypoglycemia); no other outcomes were adjusted.

Patient follow-up: Among the 1002 mothers approached, 588 provided consent for the study. 72 of these infants were not enrolled secondary to ineligibility/other reasons. A total of 242 infants became hypoglycemic, of which 237 infants were analyzed (97.9%). This included 118 infants in the dextrose gel group and 119 infants in the placebo gel group. The cohort was followed to two years of age and their neuro-developmental outcomes are published separately6.

MAIN RESULTS

Highlighted Maternal Demographics

Dextrose Gel

(n=115)

Placebo Gel

(n=115)

Maternal age (years)

29.2 (6.0)

30.2 (6.5)

Gravity

2 (1-11)

2 (1-12)

Parity

1 (0-7)

1 (0-10)

Diabetic

46 (40%)

46 (40%)

Intended Feeding Method – Breast

114 (99%)

109 (95%)

Highlighted Infant Demographics

Dextrose Gel

(n=118)

Placebo Gel

(n=119)

Males

48 (41%)

65 (55%)

Birthweight (grams)

3091 (824)

3031 (782)

Vaginal Birth

73 (62%)

74 (62%)

Glucose concentration at time of randomization (mmol/L)

2.2 (1.1-2.5)

2.2 (0.9-2.5)

Hypoglycemia Risk Factors

IDM

Late Preterm (35-36 weeks)

Birthweight

<2500g

<10%ile

>4500g

>90%ile

Other

46 (39%)

41 (35%)

30 (25%)

13 (11%)

12 (10%)

26 (22%)

6 (5%)

46 (39%)

49 (41%)

32 (27%)

19 (16%)

10 (8%)

27 (23%)

4 (3%)

Highlighted Results

Primary Outcome

Dextrose Gel

(n=118)

Placebo Gel

(n=119)

Relative Risk

(95% CI)

p value

Treatment Failure

16 (14%)

29 (24%)

0.57 (0.33-0.98)

0.04

Secondary Outcomes

Feeding

Breastfed Babies

Babies receiving expressed breastmilk

Babies receiving infant formula

112 (95%)

100 (85%)

68 (58%)

113 (95%)

97 (82%)

72 (60%)

1.00 (0.94-1.06)

1.04 (0.93-1.17)

0.95 (0.77-1.18)

0.99

0.60

0.69

Admitted to NICU

Babies (n)

For hypoglycemia (n)

45 (38%)

16 (14%)

55 (46%)

30 (25%)

0.83 (0.61-1.11)

0.54 (0.31-0.93)

0.24

0.03

Dextrose Administration

Study Gel

Open-label Gel

Intravenous Bolus

Intravenous Infusion

Dose of Total Dextrose from all Sources (g/kg)

118 (100%)

6 (5%)

7 (6%)

8 (7%)

0.3 (0.2-11.4)

119 (100%)

13 (11%)

13 (11%)

17 (14%)

0.0 (0.0-16.2)

0.47 (0.18-1.18)

0.54 (0.23-1.31)

0.47 (0.21-1.06)

0.20 (0.19-0.23)

0.15

0.24

0.09

<0.0001

Duration of low interstitial glucose concentrations

Babies with continuous glucose monitoring(n)

Duration (min per baby)

Proportion of time (%)

32 (27%)

81 (0-840)

3.0% (0.0-31.8)

36 (30%)

164 (0-1064)

6.1% (0.0-37.9)

(-7.0-124)

(-0.2-4.6)

0.23

0.13

CONCLUSION

The authors conclude that administration of 40% dextrose gel to hypoglycemic infants between 35-42 weeks gestational age and less than 48-hours old is both safe and easy to administer and results in decreased treatment failure as well as less admissions to the NICU for hypoglycemia.

COMMENTARY

Neonatal hypoglycemia is common and often under-recognized, as found with use of continuous glucose monitoring by Harris et al., where 81% of 265 episodes of low interstitial glucose concentrations detected with continuous monitoring were not detected by routine clinical practice of intermittent blood glucose measurements1. Recommendations for screening and treatment have been put forth by both the American Academy of Pediatrics and the Pediatric Endocrine Society2,3. Treatment of neonatal hypoglycemia that does not respond to feeding alone has typically included admission to the neonatal intensive care unit (NICU) and administration of intravenous dextrose via bolus and/or continuous dextrose infusion. This practice often results in separation of the baby from its parents and likely impacts the establishment of breastfeeding. Therefore, the potential for treatment of neonatal hypoglycemia with oral dextrose gel to prevent NICU admissions is promising.

This clinical trial’s identification of infants with low glucose concentrations included screening patients with several clinical risk factors within the first hour after birth, pre-feed every 3-4 hours for the first 24 hours and then every 6-8 hours for the subsequent 24 hours. This data was combined with continuous glucose monitoring to identify episodes of rebound or recurrent hypoglycemia, which were not significantly different between groups. The results show that administration of buccal 40% dextrose gel along with encouraging feeding in infants with neonatal hypoglycemia resulted in decreased treatment failure compared to the placebo controlled who were also encouraged to feed4. The secondary outcomes evaluated include provider-centered outcomes, resource-centered outcomes as well as proximal feeding outcomes at two weeks, with fewer babies in the dextrose gel group receiving formula, 5 (4%), compared to those in the placebo group, 15 (13%), 95%CI (0.13-0.90), p=0.03. In addition, although not specifically powered to detect this difference, fewer infants were admitted to the NICU for the diagnosis of hypoglycemia, 16 (14%) vs. 30 (25%), 95%CI (0.31-0.93), p=0.03 with a NNT equal to 9.

The benefits of oral dextrose gel include ease and rapidity of administration, good tolerance, low cost of administration and no increased risk of recurrence or rebound hypoglycemia. One limitation to consider is that the study subjects were recruited from a single center. In addition, other outcomes of interest not mentioned include degree of failure of infants who became hypoglycemic as well as duration of stay for infants ultimately admitted to the NICU. Their population included extremely high rates of breastfeeding, which may not be translatable to other populations and did not mention inclusion of infants receiving of donor breastmilk, which is becoming increasingly more common5. The two-year follow-up data published separately show similar rates of neurosensory impairment and processing difficulty between the treatment and placebo groups with a 78% follow-up rate6. Overall, this study provides support for the implementation of oral dextrose gel for infants ages 35-42 weeks gestation who are at risk for neonatal hypoglycemia, in order to prevent NICU admissions for hypoglycemia and potentially increase breastfeeding rates.